Abstract The development of early detection approaches is fundamental to reduce the growing cancer burden. Cellular accumulation of genetic mutations is believed to be the foundation of tumor development, however, there is a fundamental lack of knowledge regarding the earliest stages of tumorigenesis and whether certain cell populations may be more predisposed to acquire initial driving mutations. Stem cells are long-lived cells which reside in tissues and serve as a regenerative pool that actively maintain normal homeostasis and can repair tissue after injury. Accumulating evidence indicates that stem cells may also serve as the cells of origin for tumorigenesis in certain tissues and generate clonal expansions of mutated cells which could be more susceptible to further genetic insults over time. As it is not feasible to address the evolving mutational burden of stem cells in tissues of human individuals, this study will exploit mouse dorsal skin, a highly informative regenerative model system with well characterized and distinct stem cell populations. The dynamic mutation co-occurrence profiles of specific skin mouse stem cell populations will be determined following exposure to known carcinogens utilizing a customizable, single cell DNA-sequencing platform. This approach will identify whether certain mutational profiles are selectively enriched and tolerated in specific stem cell populations over long periods of time in functionally normal tissue following carcinogen exposure. The approach used by this study could easily be adapted to screen many different chemical exposures and has the potential to detect the earliest signs of cancer in similar epithelial tissue systems with shared stem cell populations such as the lung and intestine ? which are often exposed to long term environmental and chemical insult - before tumors are evident and determine distinct carcinogen-exposure signatures in cells.